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Clonal duplication of a germline PTPN11 mutation due to acquired uniparental disomy in acute lymphoblastic leukemia blasts from a patient with Noonan syndrome

Leukemia volume 21, pages 1303–1305 (2007)Cite this article

Noonan syndrome (NS; MIM 163950) is a common autosomal dominant disorder characterized by short stature, distinct facial features and congenital cardiac defects.1 In approximately 60% of NS cases, a heterozygous gain-of-function mutation can be identified in one of three genes: mutations are found in PTPN11, SOS1 or KRAS in 50, 10 and <5% of cases, respectively.1 The PTPN11 gene codes for SHP-2, a non-receptor tyrosine phosphatase that regulates multiple responses including proliferation, differentiation and migration. SHP-2 relays growth signals from stimulated growth factor receptors to other signaling molecules, including Ras. Ras is activated by the guanosine nucleotide exchange factor SOS1 and functions as a molecular switch, cycling between an inactive GDP-bound and an active GTP-bound state to control fundamental cellular pathways.2

Two of the three known NS genes, PTPN11 and KRAS, are well-known proto-oncogenes and specific somatic mutations of these genes are detected in cancer cells.1, 2 This favors the notion that NS predisposes to malignancy. Indeed, infants with NS that harbor specific germline mutations in PTPN11 (e.g., T73I) or in KRAS (T58I) are predisposed to develop myeloproliferative disease (MPD) resembling juvenile myelomonocytic leukemia (JMML).1 Myeloproliferation is generally self-limiting, implicating that NS-associated mutants disrupt hematopoiesis only during early stages of development. When the proliferating clone acquires additional genetic abnormalities, the disorder may become aggressive and lethal.

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Acknowledgements

We thank Marcel Tauscher and Cornelia Klein for their excellent technical assistance. We are grateful to Dr Mwe Mwe Chao for critical comments.

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Authors and Affiliations

  1. Department of Pediatrics, University of Freiburg, Freiburg, Germany

    A Karow, C Flotho, C M Niemeyer & C P Kratz

  2. Institute of Cell and Molecular Pathology, Hannover Medical School, Hannover, Germany

    D Steinemann, G Göhring & B Schlegelberger

  3. Department of Pediatrics, Skejby Hospital, Aarhus University, Aarhus, Denmark

    H Hasle

  4. Department of Pediatric Hematology and Oncology, Children's Hospital of Eastern Switzerland, St Gallen, Switzerland

    J Greiner

  5. Department of Pediatrics, University of Oulu, Oulu, Finland

    A Harila-Saari

  6. Institute of Human Genetics, University of Erlangen-Nuremberg, Erlangen, Germany

    M Zenker

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Correspondence to C P Kratz.

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Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

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Karow, A., Steinemann, D., Göhring, G. et al. Clonal duplication of a germline PTPN11 mutation due to acquired uniparental disomy in acute lymphoblastic leukemia blasts from a patient with Noonan syndrome. Leukemia 21, 1303–1305 (2007). https://doi.org/10.1038/sj.leu.2404651

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